Novel pyrazolo [1,5-a]pyridines

ABSTRACT

The present invention provides substituted pyrazolo[1,5-a]pyridine derivatives expressed by a compound of the general formula (I), ##STR1## (wherein: X is hydrogen atom or methyl group; R is hydrogen atom, straight or branched lower alkyl group, lower alkoxy group, lower alkylthio group, dialkylamino group, alkyleneimino group, and morpholino group; R 1  is different from R and is hydrogen atom, straight or branched lower alkyl group, lower alkoxy alkyl group, and dialkylamino group). 
     The compound of the present invention can be prepared by reacting a compound of the general formula (II), ##STR2## in which X and R are as shown hereinbefore, with a compound of the general formula (III), in which R 1  is as shown hereinbefore, 
     
         R.sub.1 COOH (III) 
    
     or with a functional derivative of the compound of the general formula (III).

The compound of the present invention can be prepared by reacting acompound of the general formula (II), ##STR3## in which X and R are asshown hereinbefore, with a compound of the general formula (III), inwhich R₁ is as shown hereinbefore,

    R.sub.1 COOH                                               (III)

or with a functional derivative of the compound of the general formula(III).

THE DETAILED EXPLANATIONS OF THE PRESENT INVENTION

In the previous patent the present inventor presented2-alkyl-3-acylpyrazolo[1,5-a]pyridines, in which 2-alkyl group wasidentical with the alkyl part of 3-acyl radical, having very interestingpharmacological properties of circulatory system (Japanese Kokai Sho No.48-97898).

Then, the present inventor continued studying on the preparations andphysiological properties of the other pyrazolo[1,5-a]pyridinederivatives and found that compounds of the present invention had moreuseful pharmacological properties than those of the previous patentsubstance.

Namely, in the present invention, a compound of the general formula(II), ##STR4## in which X and R are as shown hereinbefore, may bereacted with a carboxylic acid of the general formula (III), or with afunctional derivative of the compound of the general formula (III), inwhich R₁ is as shown hereinbefore,

    R.sub.1 COOH                                               (III)

to prepare a compound of this invention having the general formula (I),in which X, R and R₁ are as shown hereinbefore, ##STR5## having veryinteresting pharmacological properties.

In the compound of the general formula (I) and (II), R may be loweralkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl radical and so on, or lower alkoxy group such as,methoxy, ethoxy, propoxy, iso-propoxy radical and so on, or loweralkylthio group such as methylthio, ethylthio, propylthio,iso-propylthio radical and so on, or dialkylamino group such as,dimethylamino, diethylamino, ethylmethylamino radical and so on, orcyclic alkyleneimino group such as, pyrrolidino, piperazino, pipecolinoradical and so on.

In the compound of the general formula (I) and (III), R₁ may be loweralkyl group such as, methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl radical and so on, or lower alkoxy alkyl group such asmethoxymethyl, ethoxymethyl, 2-ethoxy-1-methylethyl radical and so on,or dialkylamino group such as, dimethylamino radical and so on. Afunctional derivative of the carboxylic acid of the general formula(III) may be the acid chloride, the acid bromide, the acid anhydride ora mixed-reagent such as acid amido-phosphorus oxychloride, for example,dimethylformamide-phosphorus oxychloride, dimethylacetamide-phosphorusoxychloride, N-methyl-N-phenylacetamide-phosphorus oxychloride and soon, which are known as Vilsmeier reagents.

THE PREPARING PROCEDURE OF THE COMPOUND OF THE PRESENT INVENTION

Namely, a compound of the general formula (II), in the absence of thepresence of an inert solvent such as, carbon dilsufide, chloroform,methylene chloride, nitrobenzene and so on, may be reacted withequimolecular or an excess amount of a functional derivative of thecompound of the general formula (III), in the range of 0° to the boilingpoint of a solvent and a reagent used. When the general formula (III) isa carboxylic acid, the presence of a condensing agent such as,phosphorus oxychloride, phosphorus chloride, phosphorus bromide and soon, is preferable. When the general formula (III) is an acid halide, thereaction can be carried out smoothly in the presence or absence of acatalyst such as, aluminum chloride, zinc chloride and so on. When thegeneral formula (III) is a carboxylic anhydride, it is favorable to adda Friedel-Crafts catalyst, and a few drop of concentrated sulfuric acid.

When R₁ is hydrogen atom in a compound of the general formula (I), thereaction proceeds satisfactorily by use of a Vilsmeier reagent such as,a mixed reagent of dimethylformamide and phosphorus oxychoride and soon.

Moreover, the starting materials of the general formula (II) in thepresent invention are new compounds.

When R is alkyl group in a compound of the general formula (II), thecompounds are obtained easily by heating the2-alkyl-3-acylpyrazolo[1,5-a]pyridine derivatives of the previouslyapplied compound (Japanese Kokai Sho No. 48-97898) in acidic conditionssuch as, in 30-50%(v/v) sulfuric acid.

When R is dialkylamino group in a compound of the general formula (II),the compound is obtained by decyanation in acidic conditions of3-cyano-2-dialkylaminopyrazolo[1,5-a]pyridine which is obtained byalkylation of 2-amino-3-cyanopyrazolo[1,5-a]pyridine.

When R is alkoxy group is a compound of the general formula (II), thecompound is obtained easily by alkylation of2-hydroxypyrazolo[1,5-a]pyridine with an alkylating agent in thepresence of a basic substance.

When R is alkylthio group in a compound of the general formula (II), thecompound is obtained from 2-chloropyrazolo[1,5-a]pyridine and an alkalisalt of alkyl mercaptane.

The substances of this invention expressed by the general formula (I)have very interesting pharmacological properties, especially such ascoronary dilating action (dog), cerebral dilating action (dog),stimulating of cardiac function (dog), hypotensive activity (SHR), andsmooth muscle relaxing action (trachea and small intestine).

These properties are useful as a circulatory improver, a hypotensiveagent, and an antispasmodic agent.

The effects on blood pressure and coronary flow ofpyrazolo[1,5-a]pyridines were examined respectively in spontaneoushypertensive rats (SHR) and isolated guinea pig hearts.

    ______________________________________                                        Hypotensive and Coronary Dilating Effects                                     of Novel Pyrazolo[1,5-a]Pyridines                                             ______________________________________                                                     Hypo-    Coro-                                                                tensive  nary                                                                 Effect*  Flow**                                                  Ex.          30 mg/kg 100 μg                                               No.  KC-No.  (i.p.)   (i.a.)                                                  ______________________________________                                        1    424      ++++                                                            2    428      +                                                               3    542      ++++                                                            4    436      +                                                               5    438      +                                                               6    457      +        +                                                      7    543      +++      +++                                                    8    495      ++       ++                                                     9    497      ±     ++                                                                                           i.v 188mg/kg                            10   478      ++++     ++    LD.sub.50 (mouse)                                                                      p.o 358mg/kg                            11   589      ++++                                                            12   590      ++                                                              13   587      +                                                               14   588      ++++                                                            15   577      ±                                                            16   578      ++                                                              17   549      ++++                                                            Papaverine        +++                                                         Hexamethonius                                                                           +                                                                   Guanethidine                                                                            + ++                                                                ______________________________________                                         *Change in mean blood pressure for 3 hours in unanesthetized spontaneousl     hypertensive rats (SHR) after oral administration of                          pyrazolo[1,5-a]pyridines Percent of control                                   ± : 95 - 105(%) + : 90 - 95(%) ++: 85 - 90(%)                              +++: 80 - 85(%) ++++ : - 80(%)                                                **Increasing ratio of coronary flow in isolated guinea pig hearts after       intra arterial injection of pyrazolo[1,5-a]pyridines                          + : 5 - 30(%) ++ : 30 - 60(%) +++ : 60 - (%)                             

Almost all of analogues of pyrazolo[1,5-a]pyridines showed a markedhypotensive action and a coronary dilating effect. For example, thecompounds No. 1, 3, 10, 11, 14 and 17 decreased markedly the bloodpressure in SHR, and No. 7, 8, 9 and 10 increased the coronary flow inisolated guinea pig hearts.

From these results, the substances of this invention are recognized tobe useful as hypotensive and/or coronary vasodilating agents.

For purpose of illustration only, this invention will now be illustratedby the following examples. Of course, this invention should not belimited to the following examples.

EXAMPLE 1 FOR REFERENCE Synthesis of 2-isopropylpyrazolo[1,5-a]pyridine

A mixture of 30g (0.13 mole) of2-isopropyl-3-isobutyrylpyrazolo[1,5-a]pyridine and 200 ml of 50%sulfuric acid (v/v) solution was heated at 140° C for 10 hours. Aftercooling, the mixture was added to 400g of ice-water. The solution wasneutralized with sodium hydroxide solution and extracted withchloroform. The chloroform solution was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue wasdistilled to give 8.5g (5.3 × 10⁻ ² mole) of colorless oily product, bp127.5°-129.5° C (17 mmHg).

EXAMPLE 2 FOR REFERENCE Synthesis of2-dimethylaminopyrazolo[1,5-a]pyridine

A mixture of 3.25g (1.6 × 10⁻ ² mole) of3-carbamoyl-2-dimethylaminopyrazolo[1,5-a]pyridine and 100 ml ofconcentrated hydrochloric acid was refluxed for 5 hours. After cooling,the solution was made to alkali and extracted with chloroform. Thechloroform solution was dried over sodium sulfate and concentrated. Theresidue was column-chromatographed over alumina. The elution withmethylene chloride gave crude product, which was recrystallized fromn-hexane to give 1.3g of colorless needles, mp 51°-52° C. Yield 50%.

EXAMPLE 3 FOR REFERENCE Synthesis of 2-methoxypyrazolo[1,5-a]pyridine

Sodium (92 mg) was dissolved in 5 ml of absolute methyl alcohol withmoderate cooling. To this solution 2-hydroxypyrazolo[1,5-a]pyridine (500mg) was added and then dimethyl sulfate (500 mg) was added. The mixturewas stirred for 30 min. at room temperature and refluxed for 8 hr. Thereaction mixture was concentrated to remove methyl alcohol, and waterwas added to the residue. The solution was extracted with n-hexane, andthe n-hexane solution was dried over sodium sulfate. The dried n-hexanesolution was concentrated and the residue was distilled to give 280 mgof oily product under reduced pressure.

EXAMPLE 1 Synthesis of 3-acetyl-2-isopropylpyrazolo[1,5-a]pyridine(KC-424)

A mixture of 4.2g of 2-isopropylpyrazolo[1,5-a]pyridine, 10.2g of aceticanhydride and 2-3 drops of concentrated sulfuric acid was refluxed for 7hr. After cooling, the mixture was added to 200 ml of 4M potassiumhydroxide solution and stirred for 1 hr. The solution was extracted withchloroform and the chloroform solution was dried over sodium sulfate.The dried chloroform solution was concentrated and the residue wascolumn-chromatographed over alumina to isolate objective product.Recrystallization from n-hexane gave 4.3g of colorless needles, mp 74°C. Yield 67%.

EXAMPLE 2 Synthesis of 3-acetyl-2-n-propylpyrazolo[1,5-a]pyridine(KC-428)

2-n-Propylpyrazolo[1,5-a]pyridine (4.8g) was worked up according to thesame process as shown in example 1, with acetic anhydride (10.2g) and2-3 drops of concentrated sulfuric acid to prepare the objective productof colorless prisms, mp 98°-99°. Yield 4g (63%).

EXAMPLE 3 Synthesis of 2-isopropyl-3-propionylpyrazolo[1,5-a]pyridine(KC-542)

2-Isopropylpyrazolo[1,5-a]pyridine was worked up according to sameprocess as shown in example 1, with propionic anhydride in the presenceof 2-3 drops of concentrated sulfuric acid. The same procedure as thatin example 1 afforded an oily product, bp 162°-166° (7 mmHg), whichcrystallized afterwards. Recrystallization from n-hexane gave colorlessneedles, mp 41°-42°. Yield 39%.

EXAMPLE 4 Synthesis of the 3-formyl-2-isopropylpyrazolo[1,5-a]pyridine(KC-436)

One gram of 2-isopropylpyrazolo[1,5-a]pyridine was dissolved in 0.6 mlof dimethylformamide, and 5 ml of phosphorus oxychloride was added tothe resulting solution. The reaction mixture was refluxed for 20 min.,poured into ice-water, and neutralized with potassium carbonate. Theprecipitate was collected by filtration and washed with water.Recrystallization from n-hexane gave 800 mg of colorless needles, mp81.0°-81.5°. Yield 67%.

EXAMPLE 5 Synthesis of 3-acetyl-2-isobutylpyrazolo[1,5-a]pyridine(KC-438)

2-Isobutylpyrazolo[1,5-a]pyridine was worked up according to sameprocess as shown in example 1, with an excess acetic anhydride in thepresence of a few drops of concentrated sulfuric acid, to prepare3-acetyl-2-isobutylpyrazolo[1,5-a]pyridine (bp 165°-168°/7mmHg). Yield79%.

EXAMPLE 6 Synthesis of 3-acetylpyrazolo[1,5-a]pyridine (KC-457)

Pyrazolo[1,5-a]pyridine was worked up according to the same process asshown in example 1, with an excess acetic anhydride in the presence of afew drops of concentrated sulfuric acid to prepare3-acetylpyrazolo[1,5-a]pyridine. The product was column chromatographedover alumina with benzene as an eluent to purify the objective product.Recrystallization from benzene gave colorless needles, mp 96°-97°. Yield42%.

EXAMPLE 7 Synthesis of 3-isobutyryl-2-methylpyrazolo[1,5-a]pyridine(KC-543)

2-Methylpyrazolo[1,5-a]pyridine was worked up according to the sameprocess as shown in example 1, with an excess isobutyric anhydride inthe presence of 2-3 drops of concentrated sulfuric acid to prepare3-isobutyryl-2-methylpyrazolo[1,5-a]pyridine (139°-140°/5 mmHg). Yield40%.

EXAMPLE 8 Synthesis of3-acetyl-2-isopropyl-7-methylpyrazolo[1,5-a]pyridine (KC-495)

2-Isopropyl-7-methylpyrazolo[1,5-a]pyridine was worked up according tothe same process as shown in example 1, with an excess acetic anhydridein the presence of a few drops of concentrated sulfuric acid to prepare3-acetyl-2-isopropyl-7-methylpyrazolo[1,5-a]pyridine (147°-148°/4 mmHg).Recrystallization from n-hexane gave colorless prisms, mp 67.5°-68.0°.Yield 52%.

EXAMPLE 9 Synthesis of3-acetyl-2-isopropyl-4-methylpyrazolo[1,5-a]pyridine (KC-497)

2-Isopropyl-4-methylpyrazolo[1,5-a]pyridine was worked up according tothe same process as shown in example 1, with an excess acetic anhydridein the presence of a few drops of concentrated sulfuric acid to prepare3-acetyl-2-isopropyl-4-methylpyrazolo[1,5-a]pyridine. The product wascolumn chromatographed over alumina to purify the objective product.

Recrystallization from ethyl alcohol gave colorless prisms, mp 71°-72°.Yield 65%.

EXAMPLE 10 Synthesis of 3-acetyl-2-dimethylaminopyrazolo[1,5-a]pyridine(KC-478)

A mixture of 2.3g of 2-dimethylaminopyrazolo[1,5-a]pyridine and 30 ml ofacetic anhydride in the presence of concentrated sulfuric acid wasrefluxed for 2.5 hr. After cooling, the mixture was poured into icewater. The solution was neutralized with potassium carbonate andextracted with chloroform. The chloroform solution was dried over sodiumsulfate and concentrated. The residue was column chromatographed overalumina to purify the objective product. Recrystallization from n-hexanegave colorless prisms, mp 80.5°-81.5°. Yield 700 mg.

EXAMPLE 11 Synthesis of 3-acetyl-2-pyrrolidinopyrazolo[1,5-a]pyridine(KC-589)

2-Pyrrolidinopyrazolo[1,5-a]pyridine was worked up according to the sameprocess as shown in example 10, to prepare the objective product, whichwas recrystallized from n-hexane to give colorless needles, mp59.5°-60.0°.

EXAMPLE 12 Synthesis of 3-acetyl-2-morpholinopyrazolo[1,5-a]pyridine(KC-590)

2-Morpholinopyrazolo[1,5-a]pyridine was worked up according to the sameprocess as shown in example 10, to prepare the objective product whichwas recrystallized from n-hexane-ethyl acetate to give colorless prisms,mp 164°.

EXAMPLE 13 Synthesis of 3-acetyl-2-methoxypyrazolo[1,5-a]pyridine(KC-587)

A mixture of 2-methoxypyrazolo[1,5-a]pyridine (280 mg) acetic anhydride(3 ml) and acetyl chloride (1 ml) was refluxed for 1 hr and the reactionmixture was concentrated under reduced pressure. Water was added to theresidue and the solution was made basic with potassium carbonate. Theprecipitated crystals were collected and washed with water.Recrystallization from n-hexane-ethyl acetate gave colorless needles, mp158.0°-158.5°. Yield 160 mg.

EXAMPLE 14 Synthesis of 3-acetyl-2-ethylthiopyrazolo[1,5-a]pyridine(KC-588)

2-Ethylthiopyrazolo[1,5-a]pyridine was worked up according to the sameprocess as shown in example 13, to prepare3-acetyl-2-ethylthiopyrazolo[1,5-a]pyridine which was recrystallizedfrom n-hexane to give colorless needles, mp 84°-85°.

EXAMPLE 15 Synthesis of3-(N,N-dimethylcarbamoyl)-2-methylpyrazolo[1,5-a]pyridine (KC-577)

2-Methylpyrazolo[1,5-a]pyridine (3.6g) was dissolved inN,N-dimethylcarbamoyl chloride (10.8g). Aluminum chloride (8.0g) wasadded to the resulting solution and the mixture was heated at 130° for 3hr and poured into ice water. The solution was made basic with potassiumhydroxied solution and extracted with chloroform. The chloroformsolution was dried over sodium sulfate and concentrated. The residue wasdistilled to give 1.8g of the objective product, bp 149°-150° (2 mmHg).Yield 32%.

EXAMPLE 16 Synthesis of3-(N,N-dimethylcarbamoyl)-2-isopropylpyrazolo[1,5-a]pyridine (KC-578)

A mixture of 1.6g of 2-isopropylpyrazolo[1,5-a]pyridine and 2.1g ofN,N-dimethylcarbamoyl chloride was dissolved in 20 ml of nitrobenzene.Four grams of aluminum chloride (powder) was added at room-temperatureto the resulting solution and reaction mixture was refluxed for 8 hr andconcentrated under reduced pressure. Water was added to the residue andthe mixture was made basic with potassium hydroxide solution, extractedwith chloroform. The chloroform solution was dried over sodium sulfateand concentrated. The residue was column chromatographed over aluminumto give objective product. Distillation gave colorless oil, bp 175° (2mmHg). Yield 1.1g (50%).

EXAMPLE 17 Synthesis of3-(β-ethoxy-α-methylpropionyl)-2-isopropylpyrazolo[1,5-a]pyridine(KC-549)

A mixture of 2-isopropylpyrazolo[1,5-a]pyridine andβ-ethoxy-α-methylpropionic chloride was dissolved in carbon disulfide.Aluminum chloride was added at 0° to the resulting solution. Thereaction mixture was stirred for 3 hr, and poured into water. Thesolution was made basic with potassium hydroxide solution and extractedwith chloroform. The chloroform solution was washed with water, driedover sodium sulfate and concentrated. The residue was distilled, bp171°-173° (4 mmHg). Yield 32%.

EXAMPLE 18 Synthesis of 3-acetyl-2-dimethylaminopyrazolo[1,5-a]pyridine(KC-478)

To a solution of 68g of 2-dimethylaminopyrazolo[1,5-a]pyridine in 300 mlof pyridine was added dropwise 300 ml of acetic anhydride under coolingand stirring. The mixture was refluxed for 7 hr. and then concentrated.The residue was poured into ice-water (900g) and the solution wasextracted three times with benzene (300 ml). The benzene layer waswashed with water (300 ml) and dried over anhydrous potassium carbonate.The solution was concentrated under reduced pressure and the residue wasdistilled under reduced pressure (bp 130°-150°/0.25 mmHg) to obtain 60gof the objective product, which was recrystallized from n-hexane-benzene(20:1) to give 42g of colorless prisms, mp 78°-80.5°.

Analysis: Calcd: C, 65.00; H, 6.45; N, 20.78. Found: C, 65.07; H, 6.43;N, 20.78.

The compound thus obtained was identical with that prepared in example10.

EXAMPLE 19 Synthesis of 3-acetyl-2-dimethylaminopyrazolo[1,5-a]pyridine(KC-616)

2-Diethylaminopyrazolo[1,5-a]pyridine (500 mg) was worked up accordingto the same process as shown in example 18, to prepare the objectiveproduct, which was recrystallized from n-hexane to give colorless prisms(350 mg), mp 59.5°-60.0°.

Analysis: Calcd: C, 67.50; H, 7.41; N, 18.17. Found: C, 67.64; H, 7.45;N, 18.21.

EXAMPLE 20 Synthesis of2-dimethylamino-3-propionylpyrazolo[1,5-a]pyridine (KC-617)

2-Dimethylaminopyrazolo[1,5-a]pyridine (300 mg) was worked up accordingto the same process as shown in example 18, with propionic anhydride (2ml) and pyridine (1.5 ml) to prepare the objective product of colorlessoil (200 mg: bp 103°-115°/0.05 mmHg).

Analysis: Calcd. for its picrate (mp 139°-140°, yellow prisms fromEtOH): C, 48.43; H, 4.06; N, 18.83. Found: C, 41.36; H, 4.03; N, 18.32.

EXAMPLE 21 Synthesis of2-dimethylamino-3-isobutyrylpyrazolo[1,5-a]pyridine (KC-618)

2-Dimethylaminopyrazolo[1,5-a]pyridine (150 mg) was worked up accordingto the same process as shown in example 18, with isobutyric anhydride (1ml) and pyridine (1 ml) to prepare the objective product of colorlessoil (60 mg).

What is claimed is:
 1. A compound of the general formula: ##STR6##wherein X is hydrogen or methyl; R is dialkylamino or alkyleneimino; andR₁ is different from R and is hydrogen, straight or branched loweralkyl, or lower alkoxy alkyl. 2.3-Acetyl-2-dimethylaminopyrazolo[1,5-a]pyridine. 3.3-Acetyl-2-pyrrolidinopyrazolo[1,5-a]pyridine. 4.3-Acetyl-2-diethylaminopyrazolo[1,5-a]pyridine. 5.2-Dimethylamino-3-propionylpyrazolo[1,5-a]pyridine. 6.2-Dimethylamino-3-isobutyrylpyrazolo[1,5-a]pyridine.